DE2018252A1 - New process for the production of 18-cyano-pregnane compounds - Google Patents

Description

CIBA AKTIENGESELLSCHAFT, BASEL (SWITZERLAND) Case 6731/1 + 2 / E -.

Germany

New process for the production of 18-cyano-pregnane compounds.

The present application relates to a new process for the preparation of 18-cyano-pregnane compounds, especially of 11β-hydroxy-18-cyano-20-oxopregnane compounds. · ",.

• The 18-cyano-steroids of the Pregnan range are important Intermediate products for the manufacture of pharmacological effective steroids, for example 18-oxygenated steroids and of 18-methylene steroids. For example, l8-

00 & S44 / 1970. ORIGINAL INSPECTED

Cyano-pregnane by reduction with lithium aluminum hydride, subsequent N-methylation of the primary amines obtained and Cope degradation of the corresponding N-oxides into 18-methylenepregnane transferred v / earth. By oxidation of the double bond of the 18-methylene group, e.g. by means of osmium tetroxide and subsequent cleavage with lead tetraacetate, the corresponding 18-oxo-pregnane compounds can be obtained. Pharmacologically active 18-methylene-pregnane compounds can - according to the German patent laid-open specification 1815 ^ 88 getting produced.

The 18-cyano-steroids of the pregnancy series can according to the process described in US Pat. No. 3,092,627 by reacting 20-hydroxy-20-cyano-steroids of the pregnane series with a monovalent positive iodine containing or releasing compound according to the following Partial formula scheme can be obtained:

CH.

CN OH
\ /

C CH.

Pb (COCH-). 5 4

CO CH,

The use of this general procedure offers in some cases, e.g. for connections that are in I7- and / or carry an oxygen function in the 21-position, difficult

009844/1870 _eE _ _n

* ■■■■ - ■ "OBlGlNAL INSPECTED

s, there. those in the treatment with the above iodine-containing reagents always occur as a side reaction cleavage of the C (17). > (20) or the C (20)> (21) -

• · · ■

Bond to the formation of 18-cyano-steroids via- ' weighs, so that the yields of the said Cyano-Verbincuncon are very unsatisfactory.

There has now been a new method of manufacturing ' of llß-hydroxy-18-cyano-20-oxo-pregnane compounds found, if the above-mentioned difficulties do not occur and the simple production also from in position 17- and / or 21-oxygenated derivatives- in satisfactory- * the yield allowed. This new procedure is through

ι ·

characterized in that an 11-0-nitrite of a 11ß, 20-dil.ydroxy-20-cyano-pregnane compound is irradiated with ultraviolet light fc-vA, the 11ß-kydroxy-18-cyano-20 formed from the reaction mixture -oxo-pregnane compounds isolated, and, if desired, sets free any protected hydroxy or oxo groups present or free hydroxy groups present. esterified or etherified and / or in 9 ^a - ^{unsubstituted} compounds cleaves the llj> -hydroxy group and, if desired, the resulting Δ ° '-18-cyano-pregnane compounds in a manner that is inherent in the corresponding 9 ^a ~ halogen-11ß-hydroxy-18-e; ^# ä: vo connections transferred.

The pregnane compounds to be used as starting materials can, in addition to the substituents mentioned in the II and 20 positions, also have one or more other substituents in other positions, for example free, esterified or etherified hydroxyl groups, oxo groups, halo

009844/1970 8ad _0RIGINAt

Genatoms, hydrocarbon residues, e.g. alkyl or alkenyl groups, especially methyl or methylene groups. She '. can also have double bonds, e.g. in one or '

several of the positions 1,2; 4.5; 5 # 6 * and 6.7. Under Pregnan Compounds are thus essentially saturated or unsaturated derivatives, e.g. those of the 5a or 5ß-pregnane series, or

4 5

Δ - or Δ -Pregnene, as well as the · corresponding 19-nor compounds to understand.

Particularly noteworthy are the starting materials of the formula (I) :. ·.

NG OH

ONO

(I)

wherein R, a methyl group. or a hydrogen atom, R ^ two hydrogen atoms, an oxo group or an α- or ß-

permanent, free, esterified or etherified hydroxyl group together with a hydrogen atom, R, a hydrogen atom, a lower alkyl group or a halogen atom, R ^ a free, esterified or etherified hydroxy group, or together with

QO98U / 1970

. ι

R is a dioxyalkylidene or dioxycycloalkylidene group, R ₁ . is a hydrogen atom, a free, esterified or etherified hydroxyl group or a halogen atom and X is a hydrogen or halogen atom, and which is in one or more of the positions 1,2; ^ 1.5; 5.6 or 6.7 can have a double bond. aliphatic and allcyclischen ketones, .-., such as acetone, methyl ethyl ketone, cyclohexanone and cyclopentanone in particular, with hydrocortisone, prednisolone or 9 ^a -F fluoro-prednisolone.

In these starting materials, the ester groups are preferably derived from saturated or unsaturated ones. Carboxylic acids of the aliphatic, aromatic or heterocyclic series, especially those with 1-18 Carbon atoms, e.g. formic acid, acetic acid, pro-

pionic acid, butyric acids, valeric acids, such as η-valerian acid, or trimethyl acetic acid, trifluoroacetic acid, caproic acids, such as β-trimethyl propionic acid or diethyl

acetic acid, the Oenanth-, Capryl- ,. Pelargon, caprine,

ORiGlNALiNSPECTED

009844/1970

Undccylic acids, e.g. undecylenic acid, lauric, myristic, Palmitic or stearic acids, e.g. oleic acid, or a cyclopropane, butane, pentane and hexane carboxylic acid,

e.g. cyclopropylmethane carboxylic acid, cyclobutylmethane carboxylic acid, cyclopentylethane carboxylic acid, cyclohexylethane carboxylic acid, of benzoic acid, of phenoxyalkanoic acids such as phenoxyacetic acid, of dicarboxylic acids such as succinic acid, phthalic acid, Quinolinic acid, puran-2-carboxylic acid, 5-terfc.-butyl-furan-2-carboxylic acid, 5-3rom-furan-2-carboxylic acid, 5-bromo-furan-carboxylic acid, of nicotinic acid or isonicotinic acid, or of sulfonic acids, such as benzenesulfonic acids, or of inorganic acids such as phosphoric or sulfuric acids. .. · ■; ■

An etherified hydroxyl group is particularly one that differs from alcohols with 1-8 carbon atoms derived, e.g. from lower aliphatic alkanols, such as ethyl alcohol, Methyl alcohol, propyl alcohol, iso-propyl alcohol, the butyl or amyl alcohols or araliphatic Alcohols, especially monocyclic aryl-lower aliphatic alcohols, such as benzyl alcohol, or heterocyclic alcohols Alcohols such as α-tetrahydropyranol or -furanol.

A lower alkyl group is especially a methyl group. The mentioned dioxyalkylidene group is derived in particular of lower aliphatic ketones such as acetone or methyl ketone

0098-44 / 1 * 90.

and the dioxycycloalkylidene group preferably from 5- or. 6-membered cycloaliphatic ketones such as cyclopentanone

■ ■.

and cyclohexanone, from ..

The halogen atom in the above formula (I) is in particular a fluorine or chlorine atom.

For the irradiation according to the method, solutions of the starting materials mentioned are preferably used in one Suitable organic or inorganic, inert solvent, in particular an unsubstituted or halogenated one aliphatic or cycloaliphatic hydrocarbons, such as hexane, heptane, cyelohexane, methylcyclohexane, carbon tetrachloride, Ethylene chloride or an open-chain or cyclic ether, such as isopropyl ether. Tetrahydrofuran or. Dioxane, but preferably in an aromatic hydrocarbon such as benzene or toluene, optionally in a mixture: .. "t den other solvents mentioned above.

One uses natural or for the irradiation

artificial ultraviolet light, such as that from Mercury-J.ieder or 'high pressure burners is generated. The irradiation is preferably carried out at room temperature or, if appropriate, at a lower temperature Temperature; but you can also at a slightly higher temperature

ο ratur work *. .

^ u The isolation of the

> ·. Existing process products can be used in a manner known per se J5 can be made, preferably by chromatography ο

Silica gel or alumina, whichever is desired Compounds reside in the weakly polar fractions.

ORIGINAL INSPECTED

The transfer of protected oxo or oxy groups in the corresponding free groups can be carried out in a manner known per se.

For example, ketals are cleaved by treatment with acids, preferably dilute aqueous acids, e.g. acetic acid or Perchloric acid. Etherified hydroxyl groups, such as the above-mentioned 17,21-acetals, are also hydrolyzed by acid set in freedom. Esterified hydroxyl groups are preferably removed by alkaline treatment, e.g. aqueous or split alcoholic or aqueous alcoholic solutions of alkali, rcetallhydroxyden or alkali metal carbonates.

In the 18-cyano-pregnane compounds, which according to the present process can, if desired, split off an 11β-hydroxy group in a manner known per se for example, by treatment with a dehydrating agent such as a sulfonic acid halide, e.g., mesyl chloride, are preferred in the presence of small amounts of sulfur dioxide in a tertiary base such as collidine, or an N-haloamide or ! J-haloimide, e.g. N-bromosuccinimide, and sulfur dioxide among anhydrous conditions, especially in pyridine. If desired, the 9, ll-dehydro-18-cyano-pregnane compounds thus obtained into the corresponding 9a-halogen-11ß-hydroxy-18-cyano compounds also be converted in a manner known per se. This is done, for example, by treatment with a derivative of a hypohalogenous Acid such as bromosuccinimide or bromoacetamide, e.g. in the presence of perchloric acid and, if appropriate, splitting off hydrobromic acid from the llß-hydroxy-9a-bromo prebondings thus obtained, e.g. by means of sodium hydroxide or sodium acetate, and

009844/1970

BATH ORIGINAL

Hydrochloric acid cleavage of 9SS obtained LLSs-epoxide ^V with a hydrogen halide, such as hydrofluoric or hydrochloric acid in anhydrous or aqueous medium. A particularly advantageous method for the preparation of the 9a, llß-fluorohydrins consists in splitting the 9ß * llß- ^E PO ^x yds with the addition product of hydrogen fluoride to a carbamic acid, in particular urea, which is obtained when anhydrous hydrofluoric acid is dissolved allows the substances mentioned to act.

The invention also relates to the new by the

new processes that can be prepared 11ß-hydroxy-18-cyano-20-oxopregnane compounds, in particular, those of the Pormel

in which R, - R ₅ and X have the meaning given above for formula (I) and Y is a β-hydroxy group or together with X is a double bond, and which is also in one or more of the positions 1,2j4,5j5,6 or 6.7 may have a double bond.

QQ98U / 1S70

ORIGINAL. INSPECTED

In these connections there are those who are breathed or etherified Hydroxy groups and the ketal groups, in particular those which are aioh of those mentioned above for the starting materials Acids or alcohols, and X is in particular a chlorine or Fluorine atom, Rp is an oxo group, and in particular is one Double bond in 4 »5» and optionally also in 1,2 and / or 6,7 positions.

Particularly noteworthy are the compounds that result from irradiation of the specific starting materials mentioned above and, if necessary, release of esterified or ethereal hydroxyl groups, e.g. 18-cyano-Hß-hydroxy-progesterone, IS-cyano-cortioosterone, 18-cyano-hydroortisone, the 18-cyano-prednisolone, the IS-cyano-gck-fluorprednisolon and their functional derivatives, especially their 21 esters and ethers, preferably those that differ from those above derived acids or alcohols mentioned and in particular from the lower aliphatic carboxylic acids, such as acetic acid, propionic acid, trimethyl acetic acid, the caproic acids or enanthic acids or of lower aliphatic alcohols such as ethanol, propanol, the butanols, as well as the tetrahydropyranyl and Tetrahydrofuranyl ether.

The new compounds of the above formula (I) have significant pharmacological properties. So wise In addition to mineralooortioid effects, they also have special glucooortiooids Effect on, as shown in animal experiments, e.g. on the hat. Above all, they have anti-inflammatory and anti-inflammatory properties thymolytic properties. In addition, however, they also have antibacterial and diuretic effects.

QQ9SU / 197Q

But the new connections are also valuable. Intermediate products for the production of other useful substances, in particular of pharmaceutically active compounds

fertilize. They can also be used as a feed additive. uses v / earth.

The present invention also relates to those embodiments of the method in which one of a Compounds obtainable as an intermediate at some stage and carries out the missing steps or where a starting material under the reaction conditions is formed.

The invention is described in more detail in the following examples. The temperatures are in degrees Celsius specified. "

SAD ORIGfNAI.

009844/1970

Example 1 .

.550 mg of 3-oxo-llß-nitrosyloxy-20-hydroxy-20-cyanopr§gn§n V / earth dissolved in 2JQ ml absplyfeejn Tq \ ugl and ί-Π Gi = HQr with a centrally arranged Pyrex cold finger with apparatus irradiated with a 75 watt high-pressure mercury burner while passing nitrogen through until the positive reaction disappears with diphenylamine-sulfuric acid (approx. 25 minutes). The slightly cloudy reaction solution is then washed with water, IN sodium hydroxide solution / ice and again with water / water. The wash water is extracted with an ether-methylene chloride (4: 1) mixture, the combined organic solutions are dried and evaporated in a water jet vacuum. A slightly colored crude product is obtained which, dissolved in methylene chloride, is filtered through 10 times the amount by weight of neutral aluminum oxide (activity II). After recrystallization of the evaporated filtrate from methylene chloride / ether, the pure llß-hydroxy-18-cyano-3,20-dioxo-A -pregnene, melting at 258-260 °, is obtained.

The nitrite cyanohydrin used as the starting product can be prepared as follows: A solution, cooled to -10, of 1.50 g of IIβ-hydroxy-progesterone in 15 ml 0.5 ml of nitrosyl chloride is carefully added to pyridine and the mixture is left to stand at 4 ° for 10 hours. The reaction mixture is poured onto approx. 1 liter of ice-water while stirring, the

0098U / 1970

filtered off precipitate, washed with water, then dissolved in chloroform, the solution with ice-cold IN sodium hydroxide solution and washed with water, dried and in the water

Evaporated jet vacuum. The resulting crude product is
dissolved in ^ 5 ml of absolute ethanol without purification and, after adding 8.6 g of potassium cyanide, while stirring within 20 minutes at approx. 10 °, 9 ml of glacial acetic acid are added. That slowly fixed
The resulting reaction mixture is stirred for a further 4 hours at room temperature, then diluted with approx. 20 ml of water, then poured into approx. 500 ml of ice water, the

separated amorphous substance, dissolved in chloroform

taken, dried and in a water jet vacuum at approx. 35

Evaporated bath temperature. The amorphous

- 4th

nitrosyloxy-20-hydroxy-20-cyano-Δ -pregnen still contains approx.

20 % of the corresponding free 20-oxo compound can, however, be subjected to irradiation directly without purification. · ■ · ■ '-'.

0098 * 4/1970

Example 2

• A solution of 200 mg 3-OxQ-llß-nitrosyloxy-17a, 21 cyclopentylidendioxy ^ O-hydroxy ^ O-cyano-A -pregnen in 250 ml of absolute benzene are below those given in Example 1 Conditions with a 75 watt high pressure mercury torch irradiated. 10 identical batches are combined, one after the other with water, 15 # strength sodium thiosulfate solution, ice-cold IN hydrochloric acid, water, ice cold IN caustic soda and Washed again with water, the wash water with ether, methylene chloride (4: l) mixture extracted, the organic Solutions dried and evaporated in a water jet vacuum. The amorphous crude product obtained is 30 times the amount by weight Chromatographed silica gel. With toluene-ethyl acetate- (9: 1) mixture is the llß-hydroxy-18-cyano-3,20-dioxo-

17a, 21-cyclopentylidenedioxy-A -pregnen obtained. The connection melts after being dissolved twice from methylene chloride ether at 228-229 °. . ·

The used raw material can be prepared as follows v / earth: A suspension of 10 g of hydrocortisone and 20 mg of p-toluenesulfonic acid in 1,800 ml of benzene becomes 100 ml of solvent is distilled off. 20 ml of freshly distilled 1,1-diethoxy-eyeIo-pentane are then added and the mixture is distilled Another 1000 ml of benzene are removed within 45 minutes. The clear solution v / ird then cooled to room temperature, with

0Q98A4 / 197Q -bad original

1.5 ml of pyridine were added and worked up. The resulting crude product is crystallized from methylene chloride / Purified methanol and the 17.21- melting at 212-215 °

ι ·

Ketal continues to be used directly. M ß the connection as described in Example 1 dissolved in 15 ml of pyridine and. reacted with 1.0 ml of nitrosyl chloride. The work-up yields pure 11-O-nitrite of the 17,21-ketal des Hydrocorti- "* sons, which melts at 182 ° with decomposition. A suspension of 3.0 g of the above compound in 100 ml of absolute As described in Example 1, ethanol is reacted with 18.0 g of potassium cyanide and 19.2 ml of glacial acetic acid. After work-up the 20-cyanohydrin of the nitrite of the 17,21-ketal is obtained of the hydrocortlone, which melts at 206 ° with decomposition and is irradiated directly without further purification can. . ". ·. *.

Example 3.

500 mg 3 "0xo-llß-nitrosyloxy-17a, 21-cyclopentyli-

1 k
dendioxy-20 ~ hydroxy-20-cyano-Ä '-pregnadiene are dissolved in 250 ml of absolute toluene and placed in an apparatus with a centrally arranged Pyrex cold finger at room temperature while passing nitrogen through a 75 watt high-pressure mercury burner until the positive reaction with diphenylamine-sulfuric acid

009844/1970

(approx. 30 minutes) irradiated. The work-up carried out in accordance with the details of Example 1 yields a yellowish amorphous crude product, from which, by chromatography on SiIi : T9luol, E§sigesfcor (9: 1) -OümifiQll] ΐΐαδ

llß -hydroxy -17a, 21 -eye lopentylidendioxy-18-cyano -3,20 -dioxo-

14 '

Δ '-pregnadiene is obtained, which after dissolving from methylene

chloride / ether melts at 213-214 °.

The starting material used is prepared from the known melting at 222r223 ° 17,21-Ketal of cyclopentanone with prednisolone as follows: 4.73 S of the compound are dissolved in 37 ^m l of pyridine and under the conditions in Example 1 with 1.5 ml of nitrosyl chloride reacted. The work-up yields crystalline 11-0-Nltrit of the 17,21-cyclopentanone ketal of prednisolone, which, after being dissolved in methylene chloride / ether, melts at 202-204 ° with decomposition. 4.45 g of this compound are suspended in 150 ml of absolute alcohol and reacted with 27 g of potassium cyanide and 28.5 nil of glacial acetic acid under the conditions given in Example 1. After working up, a yellowish crude product which crystallizes on spraying with ether is obtained, from which the pure 20-cyanohydrin-II-O-nitrite, which melts at 166 with decomposition, is obtained by dissolving from methylene chloride / ether.

0 0984 4/1970 ^{ßAD 0Rfe} "NAL

, 20Ί8252.

Example 4 '

A solution of 700 mg of 11β-hydroxy-17a, 21-cyclopentylidenedioxy-18-cyano-3 * 20-dioxo-A '-pregnadiene in 5.6 ml Methylene chloride and 28 ml of acetone is mixed with 56.0 mg of p-toluene sulphonic acid added and left to stand at room temperature for 17 hours. The reaction mixture is then poured onto ice water, extracted three times with methylene chloride, the organic Layer with water, saturated sodium bicarbonate solution and washed again with water / water, dried and evaporated in a water jet vacuum. The resulting crude 18-cyano-prednisolone is then purified by recrystallization from methylene chloride / methanol. Mp. 260 ° · '..

Example 5

150 mg llß-hydroxy-17aj21-cyclopentylidenedioxy-

H.

18-cyano-3,20-dioxo-A -pregnen are described as in Example 4 in acetone-methylene chloride mixture with p-toluenesulfonic acid implemented. The work-up and subsequent crystallization of the crude product from methylene chloride / ether supplies the pure 18-cyano-hydrocortisone. M.p. 258-260

009tU / 1970

Example 6

200 mg of 18-cyano-prednisolone are in 1 ml of pyridine dissolved and, after adding 0.5 ml of acetic anhydride, left to stand for 3 hours at room temperature. The usual work-up delivers 510 mg raw llß, 17a-dihydroxy-18-cyano-3.20 ^ 10X0-21-

1 4 '"
acetoxy-Δ * -pregnadiene, which is purified by dissolving from methylene chloride / ether. The purified compound melts a first time at 153-156 ⁰ and then a second time at 228 ° -229 °.

Example- 7

450 mg 3-0xo-9α-fluoro-ll-nitrosyloxy-17α, 21-cyclo-

• 14 pentylidenedioxy-20-hydroxy-20-cyano-A *. -pregnadia are in a mixture of 200 ml of toluene and 50 ml of dioxane and dissolved under

the conditions described in Examples I-3 with a High pressure mercury burner irradiated.

Final chromatography on silica gel yields crude 3 * 2O-dioxo-9a-fluoro-11ß-hydroxy-.17a, 21-cyclopentylidenedioxy-1 & -cyano-

Δ '-pregnadien, which under the conditions given in Example' 4 by treatment with acetone, and p-toluenesulfonic acid in the free 9tt-fluorine-18-cyano-prednisolone is converted. That through anschlies send acyetylation with pyridine acetic anhydride obtained 3,20-dioxo-

14 9e-fluoro-113, 173-dihydroxy <-i8-cyano-21-ao-ethoxy-A '-pregnadiene

(9a-fluoro-18-cyaho-prednisolone acetate) is made by dissolving from methylene chloride-methanol-atther cleaned. Double melting point at

■ ·

OeilU / 1170

ORIGINAL 5HSPECTED

Example 8

2.85 s are lS-cyano-prednisolone acetate dissolved in 18.5 ml of dimethylformamide and 5.7 ml of collidine and 1O ⁰ C with 2.65 g of a solution consisting of 3.18 g sulfur dioxide in 93 # 8 6 of methanesulfonyl chloride. With stirring, the mixture was heated at 35 ° internal temperature auf.-After a reaction time of 20 minutes (maximum temperature: 4l ° C) ater added dropwise at 10 ⁰ C 18.5 ml V / and extracted after strong dilution with water, twice with chloroform. The organic extracts are washed successively with ice-cold 1N hydrochloric acid, V / water, ice-cold 1N sodium hydroxide solution and again with water / water, dried and evaporated in a water-jet vacuum. The 9,11-dehydro-18-cyano-precnisolone acetate is obtained by chromatography on silica gel [solvent: toluene-ethyl acetate (70:30) mixture], which melts at 152-153 ° C. after being redissolved from methylene chloride / ether.

Example 9

1 * 7 g 9 * ü ~ D ^en ydro-l8-cyano-prednisolone acetate are used in

34 ml abs. Dioxane and 2.9 ml perchloric acid solution, (consisting of 0.4 ml of 70% perchloric acid dissolved in 5 * 5 ml of water), with stirring at room temperature within 10 minutes with a solution of 885 mg N-bread acetamide in 30 nil absolute dioxane and then added Stirred for 4 hours at room temperature. The yellow reaction solution is poured onto 15% ice-cold potassium iodide solution and twice extracted with chloroform, whereupon the organic phases behind

009844/1970

- ■ ·.-.- '■ BAD ORIGINAL

each other with 15 ^ strength sodium thiosulfate solution, water, ice-cold 1 η-hydrochloric acid, water, ice-cold 1 η-sodium hydroxide solution and washed again with water, dried with sodium sulfate and evaporated in a water jet vacuum at approx. 45 ° C. The crude bromohydrin is dissolved in 85 ml of acetone and, after adding 3 × 05 g of anhydrous potassium acetate, refluxed for 14 hours. The reaction mixture is cooled and, after dilution with water, extracted twice with chloroform. The extracts are washed in succession with water, ice-cold 1N hydrochloric acid, water, ice-cold 1 η sodium hydroxide solution and water, dried and evaporated in a water-jet vacuum. The slightly colored crude product is separated preparatively on silica gel plates. The main zone, which is visible under the UV lamp at 25 ^ m \ i , is eluted with a chloroform-methane (lsi) mixture and, after recrystallization from methylene chloride / ether, yields the pure one which melts at (211) 221-222 ° G 9ß * llß-Oxido-ie-cyano-prednisolone acetate.

Example 10

700 mg 9ßiHß ~ l8 ™ ^{oxido-cyano-t} prednisolo nacetat are introduced into 17.5 ml of hydrogen fluoride-urea adduct (see, for example US Pat. No. 3,211,758), and stirred for 5 hours under ice cooling. The reaction solution is then reduced to a mixture of 70 ml. With vigorous stirring. Poured ammonia / 300 g of ice and extracted twice with chloroform. The organic phases are washed with water, dried and concentrated in a water jet vacuum. The resulting 9 ^a " ^pluor ~ 18-cyano-prednisolone acetate is purified by crystallization from methylene chloride / methanol / ether. The compound is with the preparation described in Example 7

identical. - ■ ■■■■ '' .009844 / 1978

Claims (1)

Claims Process for the preparation of llß-hydroxy-18-cyano-20-oxo-pregnane compounds, characterized · that an 11-0-nitrite of a 11ß, 20-dihydroxy-20-cyanopregnane compound with; irradiated with ultraviolet light, the 11ß-hydroxy-18-cyano-20-oxo-pregnane compound formed from the reaction mixture isolated, and, if desired, protected hydroxy or oxo groups present in freedom sets or esterifies existing free hydroxyl groups or etherified and / or in 9a-unsubstituted compounds the llß- 9 Hydroxyl group is split off and, if desired, the Δτ '18-cyano -preghan compounds obtained are converted in a manner known per se into the corresponding 9 ^a ~ hemogen-11ß-hydroxy-18-cyano compounds. · ". 2 »The method according to claim 1, characterized in that that a solution of the starting materials in an inert organic or inorganic solvent is irradiated. · ' 3. The method according to any ^one of claims 1-2, characterized in that irradiation is carried out with artificially generated ultraviolet light. . · 009844/1970 Ψ · · ancestors according to any one of claims 1-3, characterized characterizedj that one is used to generate the ultraviolet light High pressure mercury or girdle pressure torch used. 5. The method according to any one of claims l- ^l \, characterized ,, that one at room temperature or lower
Irradiated temperature. ■ ' 6. The method according to any one of claims 1-5. · Thereby characterized in that the solvent used is an aliphatic, cycloaliphatic or aromatic hydrocarbon used. . '.. · ■' " 7. 'The method according to claim 6, characterized in net that one uses benzene or toluene. 8 .. The method according to any one of claims 1-5 » characterized in that the solvent used is an open-chain or cyclic ether. 9. · The method according to claim 8, characterized in that isopropyl ether, tetrahydrofuran or dioxane
used. '' · · 10 *. 'The method according to any one of claims 1-9, characterized characterized in that the process product present in the irradiation solution is selected in a manner known per se. 009844 / 1Ö70 the roaction mixture isolated « ORlGiNAL INSPECTED 11. The method according to claim 10, characterized in that that the product is isolated by chromatography ;; ' 12. The method according to one of claims 1-11, characterized marked / that one which is to be carried out if necessary Release of esterified !! or etherified hydroxyl groups performs in a manner known per se * ■ iy ,. Process according to one of Claims 1-11, characterized in that the esterification of free hydroxyl groups, which may be carried out, is carried out in a manner known per se ι. perform. · _V. . . .... 14. The method according to any one of claims 1-11, characterized in that the exposure products obtained for cleavage of the 11-hydroxyl group to be carried out if necessary with a sulfonyl halide in the presence of a tertiary organic Base treated »; . . ■■ _. ":.-._ ■.. 15 «The method according to any one of claims 1-11, characterized • marked that the exposure products obtained for optionally to be carried out cleavage of the 11-hydroxy group with an N-haloamide or imide in the presence of a tertiary base and treated by sulfur dioxide under anhydrous conditions. 009844/1970 l6. Method according to claim l4, characterized in that that mesyl chloride is used in the presence of collidine. 17. The method according to claim 15, characterized in that that one uses N-bromosuccinimide in the presence of pyridine. 18. The method according to any one of claims 1-11 and 13-17 *, characterized in that 9,11-dehydro-compounds obtained are treated with bromosuccinimide or bromoacetamide in the presence of • perchloric acid and from the obtained 9 ^a »Hß" ■ bromohydrin, Splitting off hydrogen bromide by means of an alkali hydroxide or alkali acetate. 19. The method according to any one of claims 1-11 and I3-I8, characterized in that one obtained 9ßjHß-epoxies splits by means of the Ad.duk.tes of hydrogen fluoride to urea. 20. The method according to any one of claims 1-19 *, characterized in that a compound of the formula is used as starting materials ONO 2 "5 (D - 1. 0Q98U- / 1970 BATH used, in which Π, a methyl group or a _{hydrogen atom, R 2} two hydrogen atoms, an oxo group or a 'α ¹ - or β-position, free, esterified' or etherified hydroxy group together with a hydrogen atom, TL a-water * - material atom, a lower _{alkyl group or a halogen atom, Rj 1} ■ · ■ a free, esterified or etherified hydroxy groups or together with Rj- a dioxyalkylidene or dioxycycloalkyl! - dengruppe, Rj- a hydrogen atom, a free, esterified or etherified hydroxy group or 'is a halogen atom and X is a hydrogen or halogen atom, and which is in one or more of the positions 1,2; 4.5 * 5.6 or 6.7 can have a double bond. ·. '* · " 21. The method according to any one of claims 1-20, characterized in that that one uses compounds of the formula mentioned in claim 20, in which the esterified Hy- ■ Derive hydroxy groups from aliphatic, cycloaliphatic, aromatic or heterocyclic acids with 1-18 carbon atoms. 22. The method according to any one of claims 1-20, characterized in that compounds of the " Compounds used in which the etherified hydroxyl groups are derived from alcohols with 1-8 carbon atoms. 23 · Process according to one of Claims 1-20, characterized in that compounds of the compounds mentioned in Claim 20 in which a lower alkyl group is a ^ methyl- _{s are used} ■ ·. ■. ■■■ ί group means. 000844/1970 BATH 24. The method according to any one of claims 1-20, characterized in that compounds of those mentioned in claim 20 are used Compounds used in which a dioxyalkylidene group is derived from a lower aliphatic ketone. 25 · The method according to any one of claims 1-20, characterized characterized in that compounds of the compounds mentioned in claim 20 in which a dioxycycloalkylidene group is used differ from a 5- or 6-membered cycloaliphatic Ketone derived. 26. The method according to any one of claims 1-20, characterized in that compounds of the formula (I) of claim 20 used as starting compounds in which X is chlorine or fluorine. 27. The method according to any one of claims 1-20, characterized in that the 11-0-nitrite of the 20-cyanohydrin used by llß-hydroxy-progesterone as a starting material. 28. The method according to any one of claims 1-20, characterized in that the 11-0-nitrite of the 20-cyanohydrin of a corticosterone-21-ester used as a starting material. 009844/1970 29 · The method according to any one of claims 1-20, characterized characterized in that one is an 11-O-nitrite of a 20-cyanohydrin of a lT ^ l -cyclic ketal of a lower aliphatic or cycloaliphatic ketones with hydrocortisone or prednisone, used as raw material. 30. The method according to any one of claims 1-20, characterized in that an 11-O-nitrite of a 20-cyanohydrin of the 9 ^a "F ^ ^u ° r-prednisolone is used. Connections of the FormeJL wherein R..a methyl group or a hydrogen atom, R ₂ two hydrogen atoms, an oxo group or an α- or β-position, free, esterified or etherified hydroxyl group together with a hydrogen atom, R, a hydrogen atom, a lower alkyl group or a halogen atom, R ^ a free, esterified or etherified hydroxyl group, or together with R, .. a dioxyalkylidene or dioxycycloalkylidene group, R_ a hydrogen atom, a free, esterified or etherified 009844/1970 ORIGINAL INSPECTED IS Hydroxy group or a halogen atom, X a hydrogen or Halogen atom and Y a β-hydroxy group or together with X represents a double bond, and which represents a double bond in one or more of the positions 1, 2, 4, 5, 5, 6 or 6, 7 can show «. 32. ■ Compounds according to claim 31 * characterized in that that the esterified hydroxyl groups are aliphatic, cycloaliphatic, aromatic or heterocyclic Derive acids with 1-8 carbon atoms. 33 Compounds according to Claim 31 * characterized in that that the esterified hydroxyl groups are derived from nicderaliphatic acids. 3 ^ .. Compounds according to claim ~ $ 1, characterized in that the etherified hydroxyl groups are derived from alcohols with 1-8 carbon atoms. 35 · Compounds according to claim J) I, in which a lower alkyl group is a methyl group ". 36 · Compounds according to claim 31 * in which a dioxyalkylidene group is derived from a lower aliphatic ketone. 0 ^ ^{9844/1970 BAt} > original yjl Compounds according to claim 31 * in which a dioxy · cycloalkylidene group is derived from a 5- or 6-membered cycloaliphatic ketone. .. ■■ / ■ _ · ........ - 38.. Compounds according to claim 31 * wherein X is ChXop or Means fluorine. . »" 39. The iö-cyano-llß-hydroxy-progesterone. ^ * 40. The iS-cyano-corticosterone and its 21-ester » 41. The 18-cyano-hydrocortisone and its 21-esters. . * t ■ ■ ". · ■ ' 42. The iS-cyano-prednisolone and its 21-esters. 43. The IS-cyano ^ a-fluoro-prechnisolonuM its 21-ester. 44.; Esters according to claims 38-43, wherein the ester groups derive from carboxylic acids with 1-8 carbon atoms. . '' 45th S | ster according to claims 38-43 in which the Estonians *? - groups are derived from low-disraliphatic acids. WSPiCTED * t6. Pharmaceutical preparations containing a compound the formula. . ' ON. wherein, R _{1 is} a methyl group or a hydrogen atom, R _{2 is} two • hydrogen atoms, an oxo group or an α- or β-position, free, esterified or etherified hydroxy group together.mit a hydrogen atom, R-. a hydrogen atom, a lower alkyl group or a halogen atom, R ₂ , a free, esterified or etherified hydroxy group or together with R, a dioxyalkylidene or dioxycycloalkylidene group, R, a hydrogen atom, a free, esterified or etherified hydroxy group or a halogen atom. , X is a hydrogen or halogen atom nnü ? a β-hydroxy group or together with X represents a double bond, and which is in one or more of the positions 1,2; 4.5; 5.6 or 6.7 can have a double bond "as an active ingredient together" with a pharmaceutical carrier material. '■ -] ORKMHAL 47. Pharmaceutical preparations according to claim 46, characterized characterized in that they contain one of the compounds mentioned in claims 32-45 as an active ingredient together with a pharmaceutical carrier material. 48. Pharmaceutical preparations according to claims 46-47 for parenteral administration in the form of injections ^ solutions in ampoules ·. · ■ -.- · " 49. Pharmaceutical preparations according to the claims 40--7 for oral application in the form of tablets. Linguettes or coated tablets. 50. Pharmaceutical preparations according to the claims 46- ^ 7 for local application in the form of ointments or Creams. 5I- .Futter containing one of the claims 32-4 = claimed connections. 52. The in the. Examples of new compounds described 53. Those obtained by the method of claims I-30 Links. ^BA 0 ORIGINAL 009844/1970 5 * 1. Those obtainable by the process of claims I-30 Links. 0098 4 4/1970 bad original